Since the 20th century, influenza infectious diseases have claimed a huge number of victims (Nat. Immunol 7,449-455, 2006). Although it has been possible to predict variant viruses that will prevail in the season next year due to the preparation for seasonal influenza by the Global Influenza Surveillance Network (GISN), there still remains uncertainty in that the predicted vaccine strains do not correspond to the epidemic strains of the following year or recombinant vaccine strains are impossible to mass-produce. The epidemic of the Fujian strain from 2003 to 2004, a variant of vaccine strain A/Panama/2007/99, caused the annual average infant mortality rate to rapidly increase from 9 to 153 in the following year (N Engl J Med 350,218-220, 2004). This may be a representative example in which the predicted vaccine candidate strain does not match to the epidemic strain. Unfortunately, the known existing egg-based production process failed to overcome the above disadvantages in the production of influenza vaccine.
The Spanish flu notoriously increased the mortality rate due to unprecedented extreme toxicity. In addition, appearance of highly pathogenic avian influenza (HPAI) H5N1, which has similar pathogenicity to the Spanish flu highlighted the fact that it is very difficult and impossible to prepare for infectious diseases that will prevail in the future (Nature 437, 889-893, 2005). The Global Influenza Surveillance Network (GISN) has conducted epidemiological survey of H5N1 since 2004, and regularly updated the vaccine candidates. Most vaccine manufacturers have developed H5N1 prepandemic vaccine according to the prediction of GISN, and currently, this is the only measure.
The pandemic H1N1 and highly pathogenic avian influenza (HPAI) H5N1 in 2009 caused concerns that highly pathogenic and highly infectious recombinant influenza reassortants might appear in the future. Eventually, only the universal influenza vaccine capable of preventing infection by broad types of viruses would be the ultimate solution. There was a study of proposing a M2 protein as a promising target for universal influenza vaccine (Nat Med 5, 1157-1163, 1999). Since the M2 protein exhibits a significant level of expression on a surface of the cell infected with virus, it can prevent disease or death due to highly pathogenic influenza viruses by using anti-M2 antibodies in cell mediated immunity for removing the cells infected with viruses, but there are some limits therein.
In addition, the combinations of adjuvant agents, virus-like particles (VLP), or inactive seasonal influenza vaccine, for enhancing immunogenicity of M2, are being investigated.
Recently, a highly conserved hemagglutinin (HA) stem region of the influenza virus is drawing attention, and a relatively conserved HA stem is receiving attention as an attractive target capable of neutralizing viruses broadly. Studies about new vaccines against different types of influenza by using these among several groups are being conducted. However, anti-HA stem antibodies have relatively low neutralization activity similarly to the anti-M2 antibodies because they are not direct neutralizing antibodies. Therefore, as long as there are not other defense cooperation means in an antibody-meditated cell immunity aiming on defense, the anti-HA stem antibodies are effective only when the challenge dose is low. Various approaches for T cell-based vaccine have been attempted even though there were no commercially successful cases. Recent studies about HIV and HCV vaccines represented several promising antigen delivery means for inducing broad and active T cell immunity at the time of defense against highly variable viruses. According to the results of study about historical events of the Asian influenza, which was conducted in Cleveland in the year 1957, it can be found that the presence of cross-reactive memory T cells induced by the existing infected viruses has a defense effect even when hetero-subtypic influenza newly prevail. T-cell response has been supposed as a cross defense immune reaction against influenza infection in many clinical researches and animal studies including ferrets and monkeys. The increase in T-cell immunity due to re-infection by hetero-subtypic influenza viruses eventually showed that, the higher the T-cell immunity, the more efficient the defense against highly pathogenic influenza infection. Many research groups have studied antigen delivery methods by highly conserved internal proteins or epitope of influenza virus, such as NP or M1, by using DNA, adenovirus, poxvirus, or live attenuated virus.
Epstein researchers showed that recombinant adenovirus expressing NP and M2 had surprising efficacy in the defense against hetero-subtypic viruses when intranasal administration of vaccine was conducted and a fatal dose of challenge was attempted. T-cell vaccine has an advantage of fast induction for defense immunity, and in particular, the defense immunity is induced in one week after immunization. Many studies have proved that vaccinia virus has promising possibility as a T-cell vaccine vector.